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Abstract

Aim:

Bisphenol-A (BPA) is an endocrine disrupting compound and may exacerbate or induce allergic diseases. To the best of our knowledge, there is little evidence regarding the effects of BPA exposure on allergic rhinitis (AR) in children. In the present study, we sought to examine whether exposure to BPA in children is associated with AR.

Methods:

This study was designed as a case controlled clinical study. 140 children diagnosed as allergic rhinitis and 140 healthy children as control group were recruited. BPA, interleukin-4, interleukin-13, total IgE and interferon-gamma levels were determined. Skin prick tests were performed in patient group. Total nasal symptom score and ARIA classification were used to predict disease severity.

Results:

Serum IL-4, IgE and BPA levels of children with allergic rhinitis were found to be significantly higher than the control group. BPA and IL-4 levels were significantly higher in moderate to severe-persistent group. There was a positive correlation between total nasal symptom scores and Bisphenol A levels in children with allergic rhinitis.

Conclusions:

The present study is the first to observe statistically significant relationship between BPA concentrations and allergic rhinitis in children. Also increased levels of BPA are associated with disease severity.

Keywords

Endocrine disrupting chemicals rhinitis allergic child bisphenol A

Introduction

Allergic Rhinitis (AR) is an inflammatory, IgE-mediated disease characterized by nasal congestion, rhinorrhea (nasal drainage), sneezing, and/or nasal itching.¹ Many studies have shown that AR symptoms are bothersome and impair psychosocial wellbeing and quality of life of patients,² and furthermore cause a considerable socioeconomic cost. Since allergic rhinitis is one of the most common disorders among children a fuller understanding of its interaction with environmental exposures is essential.

Endocrine disrupting chemicals are substances that interfere with the endocrine system and metabolism, influencing public health as well as the health of individuals.³ Bisphenol-A (BPA) is an endocrine disrupting compound and plays an important role in daily life due to its widespread use worldwide in many consumer products over the past 30 years.⁴ In particular, BPA is widely used in toys, baby bottles, plastic storages, heating containers for food and beverages, the lining of metal cans, medical equipment, consumer electronics and dental sealants and composites. Children’s exposure to BPA is through oral, dermal and respiratory routes.⁵ BPA has been associated with many adverse health effects, including diabetes, obesity, reproductive disorders, cardiovascular diseases, birth defects, asthma, atopic diseases and breast cancer.^6,7 Despite there are some studies investigating the possible relationship between exposure to BPA and childhood asthma, there is a paucity of data on the role of BPA exposure in development of allergic rhinitis.⁸ Furthermore, the increase in global allergic rhinitis prevalence has occurred within approximately same timeframe as the wide spread use of industrial chemicals like BPA.⁹ Animal studies suggest that exposure to BPA can reduce levels of regulatory T cells, interferon-gamma (IFN-Ɣ), and interleukin-13 (IL-13), and increase production of interleukin-4 (IL-4) and immunoglobulin E (IgE).¹⁰ However, despite these data, the exact mechanism for BPA induced allergy is still remains unclear.

To the best of our knowledge, there is little evidence regarding the effects of BPA exposure on AR in children. In the present study, we sought to examine whether exposure to BPA in children is associated with AR.

Materials and methods

This study was designed as a case controlled clinical study. 140 children, attending the outpatient clinics of the pediatrics department of the Tekirdağ Namık Kemal University, Turkey, and diagnosed as allergic rhinitis and 140 healthy children attending to the well-child outpatient clinic as control group were recruited and studied from May 2018 to August 2018.

Patients

Written informed consent was obtained from all of the legal guardians of the patients. The local ethical committee approved the study protocol (2017.84.08.08), which complied with the principles of the Helsinki Declaration.

The diagnosis of allergic rhinitis (AR) made when history and physical findings are consistent with an allergic cause (e.g., clear rhinorrhea, pale discoloration of nasal mucosa, and red and watery eyes) and one or more of the following symptoms: nasal congestion, runny nose, itchy nose, or sneezing for at least 1 month last year. Control group patients were selected from our institute’s well-child follow-up outpatient clinic.

Patient selection criteria for study group were: (i) to be diagnosed as AR; (ii) aged between 4 and 16 years old; (iii) no history of chronic diseases including asthma, atopic dermatitis, endocrine or metabolic disorders; (iv) no drug use at least 1 week prior to inclusion for the study; (v) patients with a positive skin prick test at least one allergen.

Selection criteria for control group were: (i) no history of chronic diseases including allergic rhinitis, asthma, atopic dermatitis, endocrine or metabolism disorders; (ii) aged between 4 and 16 years old; (iii) no drug use at least 1 week prior to inclusion for the study.

Prior to inclusion in the present study, all medications such as corticosteroids, antihistaminics or leukotriene receptor antagonists were prohibited for at least 1 week. Patients with infectious, vasomotor, hormonal, drug-induced and occupational rhinitis, or any complications, were excluded.

Skin prick test

The skin prick test was conducted according to a standardized method.¹¹ A total of 18 allergens were tested in this way including histamine and saline as a positive and negative control, respectively. Inhalant and food allergens which are common in our country were used as causative allergens (Allergopharma GmbH & Co. KG, Darmstadt, Germany), including two kinds of house dust mites (Dermatophagoides pteronyssinus and Dermatophagoides farina), dog and cat epithelia, cockroaches, two fungal strains (Alternaria alternate, Aspergillus fumigatus), outdoor inhalation antigens such as pollen from grass, ragweed, mugwort, alder, oak, birch and hazel and food allergens(egg yolk and whites, milk and peanut). When the positive control response exceeded 3 mm and the wheal size for the tested allergen was greater than the wheal size of the positive control, we defined the subject as being sensitized to this allergen. Drugs, such as antihistaminics, which can affect skin prick tests were withdrawn completely for 1 week before the test.

ARIA classification

The AR phenotype was classified by the physicians in accordance with the ARIA classification in children who had ever been diagnosed with AR and had nasal symptoms within the previous 12 months that was unrelated to respiratory tract infections. AR duration was thereby classified as persistent (symptoms appearing more than 4 days per week and for more than 4 weeks) or intermittent (symptoms appearing for less than 4 days a week or for less than 4 weeks). AR severity was classified as mild or moderate/severe in accordance with the presence (moderate/severe) or absence (mild) of any of the following items: (1) sleep disturbance, (2) impairment of daily activities, leisure and/or sports, (3) impairment of school performance or 4) bothersome symptoms.¹²

Total nasal symptom score

The severities of clinical symptoms were further assessed using the Total Nasal Symptom Score (TNSS).¹³ TNSS is the sum of scores for each of nasal congestion, sneezing, nasal itching, and rhinorrhea at each time point, using a four point scale (0–3), where 0 indicates no symptoms, a score of 1 for mild symptoms that are easily tolerated, 2 for awareness of symptoms which are bothersome but tolerable and 3 is reserved for severe symptoms that are hard to tolerate and interfere with daily activity. TNSS is calculated by adding the score for each of the symptoms to a total out of 12.

Questionnaire survey

A questionnaire was used for collecting data on the children’s allergic symptoms and information on duration of breast feeding, gender, birth weight, gestational age, parity, number of siblings, smoking habits of parents, pets at home and allergic history of parents.

Laboratory analysis

Venous blood samples of all children were drawn in the morning after 10–12 hours of fasting at night. All blood samples were taken with a stainless steel needle from antecubital vein and allowed to drop into glass test tubes. Anticoagulant-free blood samples taken from the patient group and the control group—10 mL from each patient—were centrifuged at 3500 revolutions per minute, and their serum contents were separated and stored at −80°C to be studied for their biochemical parameters. On the day of the study, the samples were taken out of the freezer and thawed until they reached room temperature.

Determination of BPA in sera of patients and controls was performed using the enzyme-linked immunosorbent assay (ELİSA) (Sunred Biological Technology Co, Shanghai, China). IL-4, IL-13 and IFN-Ɣ were measured using ThermoFisher Scientific ELISA kit (Massachusetts, USA). Serum total IgE levels were determined using the DRG İnternational IgE assay test kits according to the manufacturer’s prescribed protocol (New Jersey, USA).

Statistical analysis

IBM SPSS Statistics 20.0 software program (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. All values were expressed as mean and standard deviation given the non-normal distribution of variables, differences between the two groups were tested by Mann–Whitney testing. Furthermore, adjustment for potential confounding factors (total IgE, IL-4, IL-13, IFN-Ɣ or BPA) was performed using analysis of covariance. The Pearson correlation analysis was used to show possible correlation between total nasal symptom scores and BPA levels in children with allergic rhinitis. To investigate the joint effect of BPA on the allergic rhinitis symptoms and inflammatory markers, a correlation between these parameters were detected by multiple stepwise linear regression analysis. The statistical significance level was p < 0.05.

Results

The mean age of 140 allergic rhinitis children in the study group and 140 healthy children in the control group were 8.78 ± 1.51 years and 8.32 ± 1.29, respectively. The characteristics of the study population determined at the time of enrollment are summarized in Table 1.

Table 1.

Characteristics of study and control subjects.

	Allergic rhinitis (n = 140) N(%)	Control (n = 140) N(%)	P
Gender			0.823
Female	68 (48.5)	67 (47.8)
Male	72 (51.5)	73 (52.2)
Birth weight (g)			0.479
<2500	9 (6.4)	11 (7.9)
≥2500	131 (93.6)	129 (92.1)
Gestational age			0.662
<37 weeks	11 (7.9)	13 (9.3)
≥37 weeks	129 (92.1)	127 (90.7)
Parity			0.128
<2	115 (82.1)	118 (84.3)
≥2	25 (17.9)	22 (15.7)
Breast-feeding			0.118
No	18 (12.8)	16 (11.4)
<3 months	21 (15.0)	25 (17.9)
3–5 months	48 (34.3)	54 (38.6)
≥6 months	53 (37.9)	45 (32.1)
Number of siblings			0.826
0	79 (56.4)	75 (53.6)
1	46 (32.9)	49 (35.0)
≥2	15 (10.7)	16 (11.4)
Smoking habits of parents			0.476
Yes	52 (37.1)	48 (34.3)
No	88 (62.9)	92 (65.7)
Pets at home			0.617
Yes	24 (17.1)	19 (13.6)
No	116 (82.9)	121 (86.4)
Allergic history of parents			0.031^a
Yes	82 (58.6)	31 (22.1)
No	58 (41.4)	109 (77.9)

^a p < 0.05.

In our study, a high rate of allergic history was found in the parents of children with allergic rhinitis compared to the control group (p = 0.031).

140 (100%) of 140 patients with allergic rhinitis who underwent skin prick test showed positive response to at least one aero allergen. Of these patients, 83 (59.3%) had susceptibility to multiple allergens. The most common positive response was observed against house dust mites (40.7%, n = 57).

When the laboratory parameters of the study and control groups were compared, serum IL-4, IgE and BPA levels of children with allergic rhinitis were found to be significantly higher than the control group. However, there was no significant difference in INF-Ɣ and IL-13 levels between the two groups (Table 2 and Figure 1).

Table 2.

Laboratory parameters of study and control subjects.

	Allergic rhinitis (mean ± SD)	Control (mean ± SD)	p
Eozinofil (%)	3.38 ± 3.06	2.97 ± 2.31	0.297
Eozinofil (count/ml)	0.34 ± 0.31	0.28 ± 0.24	0.513
Total IgE (pg/ml)	166.4 ± 95.8	49.7 ± 32.3	0.012^a
IL-4 (pg/ml)	32.03 ± 26.45	14.28 ± 10.17	0.032^a
IL-13 (pg/ml)	9.27 ± 5.44	9.09 ± 5.13	0.755
INF-Ɣ (pg/ml)	5.79 ± 4.13	5.12 ± 3.79	0.432
BPA (pg/ml)	2225.83 ± 1321.75	445.38 ± 329.14	0.002^a

^a p < 0.05.

IgE: immunoglobulin E; IFN- Ɣ: interferon-gamma; IL-13: interleukin-13; IL-4: interleukin-4; BPA: bisphenol A.

Figure 1.

BPA levels of patients with allergic rhinitis and controls.

In the ARIA classification of 140 patients diagnosed with allergic rhinitis, 61.2% were classified as mild-intermittent, 17.8% moderate to severe-persistent, 9.1% mild-persistent and 2.8% moderate to severe-intermittent.

140 patients followed with the diagnosis of allergic rhinitis were divided into four groups according to the ARIA classification. When these four groups were compared among themselves according to the levels of BPA and inflammatory markers, BPA and IL-4 levels were significantly higher in moderate to severe-persistent group (p < 0.05) (Table 3).

Table 3.

Inflammatory markers and BPA in children classified according to ARIA.

	Mild (n = 106)		Moderate to severe (n = 34)		P
	Intermittent (n = 86)	Persistent (n = 20)	Intermittent (n = 9)	Persistent (n = 25)	P
Eozinofil (%)	3.12 ± 3.01	3.84 ± 2.98	3.04 ± 2.98	3.41 ± 3.07	0.329
Eozinofil (count/ml)	0.31 ± 0.29	0.37 ± 0.31	0.34 ± 0.28	0.35 ± 0.32	0.587
Total IgE (pg/ml)	81.7 ± 41.4	88.4 ± 38.1	92.8 ± 45.1	98.3 ± 46.1	0.719
IL-4 (pg/ml)	28.56 ± 20.47	32.91 ± 26.93	29.43 ± 21.74	43.18 ± 28.45	0.012^a
IL-13 (pg/ml)	8.91 ± 5.24	8.75 ± 4.99	9.21 ± 5.48	9.58 ± 4.92	0.823
INF-Ɣ (pg/ml)	5.64 ± 4.11	5.67 ± 4.17	5.44 ± 4.21	6.12 ± 3.98	0.615
BPA (pg/ml)	1668.17 ± 924.91	1829.97 ± 1071.15	1741.87 ± 1128.63	2487.93 ± 1368.31	0.023^a

^a p < 0.05.

The mean total nasal symptom score of 140 children with allergic rhinitis was 10.3 and there was a positive correlation between total nasal symptom scores and Bisphenol A levels in children with allergic rhinitis. In other words, as the BPA levels increased, the total nasal symptom scores of the children with allergic rhinitis also increased. The Pearson correlation analysis graph showing this is shown in Figure 2.

Figure 2.

Pearson correlation analysis graph showing the relationship between BPA and TNSS.

Multiple stepwise linear regression analysis showed that TNSS (β = 0.800, p = 0.000) and IL-4 (β = 0.310, p = 0.000) levels were associated with increased BPA in children with allergic rhinitis (the results of multivariate analysis are shown in Table 4).

Table 4.

Multiple stepwise linear regression analysis to evaluate correlation between BPA and other parameters within allergic rhinitis group.

Model	Beta	t	p	95% confidence interval
Model	Beta	t	p	Lower bound	Upper bound
1
(Constant)		5.246	0.000	315.792	701.204
TNSS	0.800	12.381	0.000	127.664	176.499
2
(Constant)		5.015	0.000	257.462	595.745
TNSS	0.757	13.419	0.000	122.517	165.138
IL-4	0.310	5.496	0. 000	3.465	7.394

TNSS: total nasal symptom score.

Dependent variable: BPA.

Discussion

In this case-controlled study, we investigated the effects of BPA, IgE, IL-4, IL-13 and INF-Ɣ in children with allergic rhinitis. Serum IL-4, IgE and BPA levels of children with allergic rhinitis were found to be significantly higher than the control group. However, there was no significant difference in INF-Ɣ and IL-13 levels between the two groups. BPA and IL-4 levels were significantly higher in moderate to severe-persistent group according to ARIA classification. Also, as the BPA levels increased, the total nasal symptom scores of the children with allergic rhinitis also increased.

BPA is a high trade volume chemical because it is widely used in many consumer products and exposure is almost inevitable in daily life. Studies assessing BPA exposure show that because of a dramatic increase in the use of BPA-containing products in daily life, BPA and its metabolites are present at detectable levels in nearly every persons blood, tissue and urine.⁴ Previous studies have reported that prenatal or postnatal exposure to BPA is associated with an increased risk of wheezing and asthma.^14,15 Also, there are a few studies to suggesting a possible association between atopic dermatitis in children.^6,16 However, to our knowledge, there is only one study conducted in children to evaluate the association between BPA levels and allergic rhinitis. Wang et al. found that urinary BPA-glucuronide levels at age 3 were positively associated with allergic rhinitis at age 3 and 6, but their results failed to reach statistical significance.⁶ Also children with asthma and atopic dermatitis were included in their study. In our study, we excluded children with asthma and atopic dermatitis and included only children with allergic rhinitis. We found statistically significant increase of BPA in allergic rhinitis supporting the previous study findings. Mean age of patients was higher in our group, and exposure to BPA may increase with age, and this might explain the statistical difference in our study. Also we measured the serum levels of BPA, instead of urinary levels. Beginning in 1999, studies were published to report the results of methods to measure BPA in human serum. These initial studies reported determinations solely of the unconjugated (also referred to as aglycone or parent) BPA that is the biologically active endocrine disrupting molecule.¹⁷ Endogenous hormones are evaluated clinically by the parent, hormonally active compound, not by less active or inactive metabolites, and BPA conjugates were reported to be devoid of estrogenic activity and this might effect their immunological activity. According to these studies, serum BPA seems to be a reliable marker.

The underlying mechanisms for the association between BPA exposures and allergic rhinitis remains unclear. As an endocrine disrupting chemical, BPA was suggested to induce a T helper 2 (Th2)–dominated immune response through its estrogenic activity.¹⁸ Furthermore, it was shown to have adjuvant effects on increases in ovalbumin-specific IgE levels by promoting Th2 immune responses, macrophage activation, and the production of cytokines,¹⁹ suggesting that BPA exposure can induce the onset and/or progression of allergic reactions. Also, prenatal exposure to BPA in mice has been associated with reduced levels of regulatory CD4-CD25 T cells.¹⁰ BPA exposure may influence mast cell-mediated production of pro-inflammatory mediators such as cysteinyl leukotriene, tumor necrosis factor alpha, and IL-13. These mediators are known to be associated with asthma.²⁰ But, whether other mechanisms also play a role in the association between BPA exposures and allergic diseases require further studies.

In allergic children, serum levels of IL-4 are expected to be increased.²¹ In our study, we found IL-4 levels was significantly increased in allergic rhinitis patients than the control group. Multiple stepwise linear regression analysis showed that IL-4 (β = 0.310, p = 0.000) levels were associated with increased BPA in children with allergic rhinitis. Our study implies that BPA exposures may increase IL-4 levels and may confer a higher susceptibility for allergic diseases, particularly allergic rhinitis. Multiple stepwise linear regression analysis showed that TNSS (β = 0.800, p = 0.000) were associated with increased BPA in children with allergic rhinitis. According to our study, increased levels of BPA is associated with symptom severity in allergic rhinitis. Our study is the first to observe stronger associations of BPA concentrations with allergic rhinitis symptom severity in children.

The AR and its impact on Asthma (ARIA) classification was introduced about 10 years ago and is continuously updated in different areas.^12,22 This classification gives the opportunity for a reliable evaluation of the disease severity of AR. We found BPA and IL-4 levels were significantly higher in moderate to severe group than mild group according to ARIA classification. These findings all add to evidence that environmental exposure to BPA during childhood can increase disease severity in childhood. To the best of our knowledge, this is the first study investigating the association between BPA levels and AR disease severity according to the ARIA classification. Therefore, there is no other study available as such to be compared with our results.

The major limitation in the current study is the small sample size. In addition, the selection of participants from only one center may have resulted in drawbacks in generability. Despite these limitations, our study has several strengths. It is one of the first investigations of BPA exposure in relation to allergic rhinitis in children. Also, case-controlled design and exposure assessment of objective biomarkers are the strengths of this study. Finally, to the best of our knowledge, this is the first study to investigate the BPA levels in patients only with allergic rhinitis and symptom severity.

Taken together, our study and previous investigations suggest that environmental BPA exposure during childhood may influence the development of allergic diseases. The present study is the first to observe statistically significant relationship between BPA concentrations and allergic rhinitis in children. Also increased levels of BPA are associated with disease severity. As plasticized products have become ubiquitous in homes and day care centers, more efforts are needed to reduce exposure to BPA to avoid aggravation of allergic rhinitis symptoms in children. Also, preventive measures should be introduced as early as possible for young children to avoid subsequent development of allergic diseases in children. It is believed that results of this study would facilitate basis for further prospective studies which are needed to confirm associations observed in this study.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by Namık Kemal University Scientific Research Projects Funding [NKU.BAP.02.GA.18.159].

ORCID iDs

A Nalbantoğlu

A Çelikkol

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Bisphenol A as a risk factor for allergic rhinitis in children

Abstract

Aim:

Methods:

Results:

Conclusions:

Keywords

Introduction

Materials and methods

Patients

Skin prick test

ARIA classification

Total nasal symptom score

Questionnaire survey

Laboratory analysis

Statistical analysis

Results

Discussion

Footnotes

Declaration of conflicting interests

Funding

ORCID iDs

References